MRI using hyperpolarized noble gases has been demonstrated as a viable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. The contents of this patent are hereby incorporated by reference as if recited in full herein. Albert et al. proposed several techniques of introducing the hyperpolarized gas (either alone or in combination with another substance) to a subject, such as via direct injection, intravenous injection, and inhalation. See also Biological magnetic resonance imaging using laser-polarized 129Xe, 370 Nature, pp. 199-201 (Jul. 21, 1994). Other researchers have since obtained relatively high-quality images of the lung using pulmonary ventilation of the lung with both hyperpolarized 3He and 129Xe. See J. R. MacFall, H. C. Charles, R. D. Black, H. Middleton, J. Swartz, B. Saam, B. Driehuys, C. Erickson, W. Happer, G. Cates, G. A. Johnson, and C. E. Ravin, “Human lung air spaces: Potential for MR imaging with hyperpolarized He-3,” Radiology 200, 553-558 (1996); and Mugler et al., MR Imaging and spectroscopy using hyperpolarized 129Xe gas: Preliminary human results, 37 Mag. Res. Med., pp. 809-815 (1997). See also E. E. de Lange, J. P. Mugler, J. R. Brookeman, J. Knight-Scott, J. Truwit, C. D. Teates, T. M. Daniel, P. L. Bogorad, and G. D. Cates, “Lung Airspaces: MR Imaging Evaluation with Hyperpolarized Helium-3 Gas,” Radiology 210, 851-857(1999); L. F. Donnelly, J. R. MacFall, H. P. McAdams, J. M. Majure, J. Smith, D. P. Frush, P. Bogorad, H. C. Charles, and C. E. Ravin, “Cystic Fibrosis: Combined Hyperpolarized 3He-enhanced and Conventional Proton MR Imaging in the Lung—Preliminary Observations,” Radiology 212 (September 1999), 885-889 (1999); H. P. McAdams, S. M. Palmer, L. F. Donnelly, H. C. Charles, V. F. Tapson, and J. R. MacFall, “Hyperpolarized 3He-Enhanced MR Imaging of Lung Transplant Recipients: Preliminary Results,” AJR 173, 955-959 (1999).
In addition, due to the high solubility of 129Xe in blood and tissues, vascular and tissue imaging using inhaled hyperpolarized 129Xe has also been proposed. Generally described, during inhalation delivery, a quantity of hyperpolarized 129Xe is inhaled by a subject (a subject breathes in the 129Xe gas) and the subject then holds his or her breath for a short period of time, i.e., a “breath-hold” delivery. This inhaled 129Xe gas volume then exits the lung space and is generally taken up by the pulmonary vessels and associated blood or pulmonary vasculature at a rate of approximately 0.3% per second. For example, for an inhaled quantity of about 1 liter of hyperpolarized 129Xe, an estimated uptake is about 3 cubic centimeters per second or a total quantity of about 40 cubic centimeters of 129Xe over about a 15 second breath-hold period. Accordingly, it has been noted that such uptake can be used to generate images of pulnonary vasculature or even organ systems more distant from the lungs. See co-pending and co-assigned U.S. patent application Ser. No. 09/271,476 to Driehuys et al, entitled Methods for Imaging Pulmonary and Cardiac Vasculature and Evaluating Blood Flow Using Dissolved Polarized 129Xe. Although primarily directed to inhalation delivery, this application also proposes injection of 129Xe to replace conventional radioactive tracers in perfusion imaging methods. The contents of this application are hereby incorporated by reference as if recited in full herein.
Many researchers are also interested in the possibility of using inhaled 129Xe for imaging white matter perfusion in the brain, renal perfusion, and the like. While the inhaled delivery 129Xe methods are suitable, and indeed, preferable, for many MRI applications for several reasons, such as the non-invasive characteristics attendant with such a delivery to a human subject, it may not be the most efficient method to deliver a sufficiently large dose to more distant (away from the pulmonary vasculature which is proximate to the lungs) target areas of interest. In addition, due to the dilution of the inhaled 129Xe along the perfusion delivery path, relatively large quantities of the hyperpolarized 129Xe are typically inhaled in order to deliver a small fraction of the gas to the more distal target sites or organ systems. For example, the brain typically receives only about 13% of the total blood flow in the human body. Thus, the estimated 40 cubic centimeter quantity of hyperpolarized 129Xe taken up into the pulmonary vessels from the 1-liter inhalation dose can be reduced to only about 5 cubic centimeters by the time it reaches the brain.
Further, the hyperpolarized state of the gas is sensitive and can decay relatively quickly due to a number of relaxation mechanisms. Indeed, the relaxation time (generally represented by a decay constant “T1”) of the 129Xe in the blood, absent other external depolarizing factors, is estimated at T1=4.0 seconds for venous blood and T1=6.4 s for arterial blood at a magnetic field strength of about 1.5 Tesla. See Wolber et al., Spin-lattice relaxation of laser-polarized xenon in human blood, 96 Proc. Natl. Acad. Sci. USA, pp. 3664-3669 (March 1999). (The more oxygenated arterial blood provides increased polarization life over the relatively de-oxygenated venous blood). Therefore, for about a 5 second transit time (the time estimate for the uptaken hyperpolarized 129Xe to travel to the brain from the pulmonary vessels), the 129Xe polarization is reduced to about 37% of its original value. In addition, the relaxation time of the polarized 129Xe in the lung itself is typically about 20-25 seconds due to the presence of paramagnetic oxygen. Accordingly, 129Xe taken up in the latter portion of the breath-hold cycle can decay to have only about 50% of the starting polarization (the polarization level at the initial portion of the breath hold cycle). Thus, generally stated, the average polarization of 129Xe entering the pulmonary blood can be estimated to be at about 75% of the starting inhaled polarization value. Taking these effects into account, the delivery to the brain of the inhaled 129Xe can be estimated as about 1.4 cubic centimeters of the inhaled one-liter dose of 129Xe polarized to the same level as the inhaled gas (0.75×0.37×5 cc's). This dilution reduces delivery efficiency, i.e., for remote target areas (such as the brain), the quantity of delivered 129Xe is typically severely reduced to only about 0.14% of the inhaled 129Xe. Nonetheless, at least one researcher has made coarse images of 129Xe in rat brains, but this inhalation administration delivery required large quantities of 129Xe to be inhaled over a relatively long period of time. See Swanson et al., Brain MRI with laser-polarized xenon in human blood, 38 Mag. Reson. Med., pp. 695-698 (1997). Unfortunately, the extended inhalation time period and/or associated large quantity dosage of the gas may not be desirable for certain clinical applications.
In an alternative delivery mode, Bifone et al. proposes the use of injectable formulations to deliver hyperpolarized 129Xe to regions of interest. Bifone et al., NMR of laser polarized xenon in human blood, 93 Proc. Natl. Acad. Sci. USA No. 23, pp. 12932-12936 (1996). Albert et al., supra, also describes such formulations. As described by Bifone et al., the injectable formulation consists of a biocompatible fluid in which hyperpolarized 129Xe is dissolved. Such formulations can then be injected intravenously to deliver hyperpolarized 129Xe. For fluid injection, the formulation is described as preferably formed such that the biocompatible fluid has a high solubility for xenon while also providing a relatively long 129Xe relaxation time. Examples of particular suggested biocompatible fluids include saline, lipid emulsions, and perfluorocarbon emulsions. Several researchers have shown images of fluid injectable formulations. For example, Goodson et al. have shown images of 129Xe dissolved in saline and injected into the hind leg of a rat. Goodson et al., In vivo NMR and MRI Using Injection Delivery of Laser-Polarized Xenon, 94 Proc. Natl. Acad. Sci. USA, pp. 14725-14729 (1997). Moeller et al. have also recently demonstrated venous angiography with hyperpolarized 129Xe dissolved in Intralipid® solution. Moeller et. al., Magnetic Resonance Angiography with Hyperpolarized 129Xe Dissolved in Lipid Emulsion, 41 Mag. Res. Med. No. 5, pp. 1058-1064 (1999). The Intralipid® formulation purportedly has a xenon-Otswald solubility of about 0.6 and a 129Xe relaxation time of 25 seconds in a magnetic field strength of 2.0 Tesla. In addition, Wolber et al, have also recently demonstrated PFOB (perfluorooctyl bromide) emulsions which allegedly have increased transverse relaxation times and have purportedly provided improved imaging results. Wolber et al., Perfluorocarbon Emulsions as Intravenous Delivery Media for Hyperpolarized Xenon, 41 Mag. Res. Med., pp. 442-449 (1999). In yet another injection technique, Chawla et al., have proposed the use of hyperpolarized 3He microbubbles suspended in a hexabrix solution to perform angiography on rats. Chawla et al., In Vivo Magnetic Resonance Vascular Imaging Using Laser-Polarized 3He Microbubbles, 95 Proc. Natl. Acad. Sci. USA, pp. 10832-10835 (1998).
Unfortunately, many injectable formulations can be unduly susceptible to handling and processing variables which can negatively impact the injectable formulation's commercial viability and/or clinical application. For example, the relatively short (and potentially magnetic-field dependent) relaxation time of the 129Xe in the injectable solutions can require that the 129Xe gas be dissolved into the biocompatible fluid relatively quickly and then subsequently rapidly injected to reduce the polarization loss of the formulation prior to injection. In addition, it may be difficult to predict the dissolution efficiency in a manner which can provide a reliable xenon dissolution concentration. Unreliable concentrations can, unfortunately, yield widely varying signal intensities, dose to dose. Further, because of the typically relatively quick decay associated with these formulations, a careful measurement of the final 129Xe polarization just prior to injection to determine the post dissolution polarization may not be possible. Still further, because the 129Xe is dissolved in a biocompatible fluid, sensitivity to the local in vivo environment such as blood oxygenation, tissue type, and the like, may be muted, reduced, or even non-existent. The use of such fluids or carrier agents to deliver 129Xe to selected tissues or organs can also be difficult because of the high solubility of 129Xe in the fluid compared to the tissues (its preferred affinity being to remain in the fluid rather than to migrate into the selected or targeted tissues).
In view of the foregoing, and despite the present efforts, there continues to be a need to improve the methods, products, and systems used to deliver hyperpolarized 129Xe gas to a target in vivo imaging region of interest.